Oxazolyl, isoxazolyl, triazolyl and thiadiazolyl alkyl bisamidines

ABSTRACT

Bisamidines carrying one unsaturated nitrogen heterocyclo-containing substituent, representative of which i; 1-[N&#39;-(2-(5-methyl-4-imidazolyl)methylthio)ethyl)guanidino]-8-[N&#39;-methylguanidino]octane, are histamine H 2  -antagonists.

This is a division of application Ser. No. 093,336 filed Nov. 13, 1979now U.S. Pat. No. 4,285,952, which is a division of application Ser. No.902,145 filed May 2, 1978, now U.S. Pat. No. 4,212,875.

This invention relates to bisamidine compounds, to their preparation, topharmaceutical compositions containing them, and to methods of blockingbistamine H₂ -receptors by administering these compounds.

Many physiologically active substances elicit their biological actionsby interaction with specific sites known as receptors. Histamine is sucha substance and has a number of biological actions. Those biologicalactions of histamine which are inhibited by drugs commonly called"antihistamines" of which mepyramine, diphenhydramine andchlorpheniramine are typical examples, are mediated through histamine H₁-receptors (Ash and Schild, Brit. J. Pharmac. Chemother., 27, 427(1966)), and drugs with this activity are hereinafter referred to ashistamine H₁ -antagonists. However, others of the biological actions ofhistamine ar not inhibited by histamine H₁ -antagonists and actions ofthis type which are inhibited by a compound described by Black et al.(Nature, 236, 385 (1972)) and called burimamide are mediated throughreceptors which are defined by Black et al. as histamine H₂ -receptors.Thus histamine H₂ -receptors may be defined as those histamine receptorswhich are not blocked by mepyramine but are blocked by burimamide.Compounds which block histamine H₂ -receptors are referred to ashistamine H₂ -antagonists.

Blockade of histamine H₂ -receptors is of utility in inhibiting thebiological actions of histamine which are not inhibited by"antihistamines". Histamine H₂ -antagonists are therefore useful, forexample, as inhibitors of gastric acid secretion, as anti-inflammatoryagents and as agents which act on the cardiovascular system, forexample, as inhibitors of the effects of histamine on blood pressure. Inthe treatment of certain conditions, for example, inflammation and ininhibiting the actions of histamine on blood pressure, a combination ofhistamine H₁ - and H₂ - antagonists is useful.

The bisamidine compounds of the present invention are histamine H₂-antagonists.

British Pat. Nos. 1338169, 1397436, 1398426, 1421792, 1496787 and1497260 and German Offenlegungschrift No. 2634433 disclose variousdifferent classes of compound of Structure 1: ##STR1## where Het is anitrogen-containing 5- or 6- membered heterocyclic ring such asimidazole, pyridine, thiazole, isothiazole, oxazole, triazole orthiadiazole, optionally substituted by lower alkyl, hydroxy, loweralkoxy, halogen, trifluoromethyl or amino; m is 0, 1 or 2 and n is 2 or3 such that the sum of m and n is 3 or 4; Z is sulphur or a methylenegroup; X is sulphur, CHNO₂ or NY wherein Y is hydrogen, hydroxy, loweralkyl, cyano or CONH₂ ; and R is hydrogen or lower alkyl, as beinguseful histamine H₂ -antagonists. A specific compound of Structure 1 iscimetidine(N-cyano-N'-methyl-N"-[2-((5-methyl-4-imidazolyl)methylthio)-ethylamino]guanidine),which has become a standard drug used in the treatment of duodenal andgastric ulcers.

Related compounds of Structure 2: ##STR2## where q is from 2 to 8, andthus having two amidine groups --NH--C--NH-- and two substituents eachincorporating a heterocycle, are disclosed as histamine H₂ -antagonistsin British Pat. No. 1493931 and German Offenlegungschriften Nos.2733951, 2733952 and 2733953.

It has now been discovered that a series of compounds in which the groupR in Structure 1 is replaced by a ##STR3## group, where q is an integerof from 2 to 12, have useful histamine H₂ -antagonist activity. Thisinvolves a novel conception of compounds which have a markedly differentchemical structure from those described above in that they contain twoamidine groups to one heterocyclic substituent, and which exhibit thesame type of activity as cimetidine although the two basic structuralfeatures of the molecule are not paired as in the publications referredto above. For example, one compound of this invention,1-[N'-cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]-2-[N'-cyano-N"-methylguanidino]ethane,is highly active when administered intravenously in the rat gastric acidsecretion test.

The present invention provides compounds of Structure 3: ##STR4## inwhich

Het is a 5- or 6- membered fully unsaturated heterocycle containing atleast one nitrogen atom, said heterocycle being imidazole, pyridine,thiazole, isothiazole, oxazole, isoxazole, triazole or thiadiazol, andoptionally substituted by lower alkyl, trifluoromethyl, hydroxymethyl,halogen, hydroxy, lower alkoxy or amino;

Z is sulphur or methylene;

m is 0, 1 or 2, n is 2 or 3, and m+n is 3 or 4;

R is hydrogen or lower alkyl;

each of X¹ and X² is sulphur, a nitromethylene group CHNO₂, or an iminogroup NY, where Y is hydrogen, hydroxy, lower alkyl, cyano or carbamoylCONH₂ ; and

q is from 2 to 12.

Structure 3 is representative of the several tautomeric forms in whichthe compounds can exist.

The compounds are basic and can be prepared in the form of their acidaddition salts, particularly their pharmaceutically-acceptable acidaddition salts, as well as the free bases. Likewise where the compoundhas an imino group NH, it can be prepared in a protected form from whichthe free imino group can be readily regenerated by removal of theprotecting group. An example of a protecting group is benzoyl, which isreadily removed by acid hydrolysis; the imino group in protected form isthe obvious chemical equivalent of the free imino group. A group NCN canbe converted to NH by hydrolysis but in this specification is to beregarded as excluded from protected imino groups.

In this specification by `lower alkyl` and `lower alkoxy` are meant analkyl or alkoxy group having from 1 to 4 carbon atoms: it can bestraight or branched.

Preferably the group (CH₂)_(m) is linked to a carbon atom of theheterocycle adjacent to a nitrogen atom. Preferably the heterocycle ofHet is imidazole, particularly Het- is 2- or 4- imidazolyl optionallysubstituted by lower alkyl (especially methyl), halogen (especiallychlorine or bromine), trifluoromethyl or hydroxymethyl. Especiallyvaluable are compounds where Het- is a 5-methyl-4-imidazolyl group.Other suitable groups are 2-pyridyl optionally substituted by loweralkyl (especially methyl), lower alkoxy (especially methoxy), halogen,(especially chlorine or bromine), amino or hydroxy, 3-(1,2,4)-triazole,2-thiazolyl, 3-isothiazolyl optionally substituted by chlorine orbromine, 3-(1,2,5)-thriadiazolyl optionally substituted by chlorine orbromine and 2-(5-amino-1,3,4-thiadiazolyl). Preferably m is 1, Z issulphur and n is 2. X¹ and X² can be different, but preferably they arthe same, particularly where X¹ and X² are both NY and Y is hydrogen orcyano, and where X¹ and x² are both CHNO₂. Preferably R is methyl: otherexamples of R are ethyl and n-propyl. Preferably q is 2 or 8.

Examples of specific compounds are:

1-[N'-(2-((5-methyl-4-imidazolyl)methylthio)ethyl)guanidino]-2-[N'-cyano-N"-methylguanidino]ethane,

1-[N'-(2-((5-methyl-4-imidazolyl)methylthio)ethyl)guanidino]-8-[N'-cyano-N"-methylguanidino]octane,

1-[N'-cyano-N"-(2-((5-methyl-4-imidazoyl)methylthio)ethyl)-guanidino]-2-[N'-cyano-N"-methylguanidino]ethane,

1-[N'-cyano-N"-(2-((5-methyl-4-imidazolyl)methylthio)ethyl)-guanidino]-8-[N'-cyano-N"-methylguanidino]octane,and

1-N'-(2-(5-methyl-4-imidazolyl)methylthio)ethylguanidino]-8-[N'-methylguanidino]octane.

The bisamidines of Structure 3 where Z is sulphur can be prepared by aprocess in which the units of the structure represented by Het-(CH₂)_(m)--, --Z(CH₂)_(n) NH--, --CX¹ --, --NH(CH₂)_(q) NH--, --CX² -- and --NHR(designated units 1, 2, 3, 4, 5 and 6 respectively), are broughttogether in the correct sequence using as reagents compounds of thefollowing structure

for unit 1 Het-(CH₂)_(m) Cl

for unit 2 HS(CH₂)_(n) NH₂

for unit 3 (MeS)₂ CX¹

for unit 4 NH₂ (CH₂)_(q) NH₂

for unit 5 (MeS)₂ CX²

for unit 6 NH₂ R

with, if required, interconversion of one or both groups X¹ and X², togive the groups X¹ and X² required in the endproduct.

Thus the unit 1 reagent ca be reacted with the unit 2 reagent by knownprocedures to give the unit combination 12 of structure Het(CH₂)_(m)S(CH₂)_(n) NH₂ ; this can be reacted by known procedures with unitreagent 3 to give the unit combination 123 of structure Het(CH₂)_(m)S(CH₂)_(n) NHCX² SMe; this can then be reacted by known procedures withunit reagent 4 to give the unit combination 1234 of structureHet(CH₂)_(m) S(CH₂)_(n) NHCX¹ NH(CH₂)_(q) NH₂ ; operating by knownprocedures this can be reacted with unit reagent 5 to give the unitcombination 12345 of structure Het(CH₂)_(m) S(CH₂)_(n) NHCX¹ NH(CH₂)_(q)NHCX² SMe; and finally this can be reacted by known procedures with theunit reagent 6 to give the unit combination 123456 which is thebisamidine of Structure 3.

The unit reagents have obvious chemical equivalents which can beemployed in their stead. For instance Cl in unit reagent 1 can bereplaced by bromine or arylsulphonyloxy (or other leaving groupsdisclosed in U.S. Pat. No. 4013678); and in unit reagents 3 and 5 themethylthio group can be replaced by lower alkylthio, arylthio,benzylthio, lower alkoxy, aryloxy or methylsulphinyl MeSO--.

The combination sequence can be in the reverse direction starting withthe unit reagents 5 and 6 to give the unit combination 56 of structureMeSCX² NHR, and adding the units 4, 3, 2 and 1 in that order.Furthermore, the building of the sequence can start with any othercombination of units, for instance by reacting unit reagents 4 and 5 togive the 45 combination unit NH₂ (CH₂)_(q) NHCX² SMe, and addingsuccessively units 6, 3, 2 and 1. Where X¹ and X² are the same, the sameunit reagent can be used to add units 3 and 5 simultaneously to adiamine providing unit 4. The Examples below illustrate a wide varietyof combination sequences: for instance Examples 20, 31 and 32 takentogether show the sequence 4+56, 3+456, 2+3456 and 1+23456.

Preferably the combination sequence starts with a combination unit 12 ofstructure Het-(CH₂)_(m) S(CH₂)_(n) NH₂ (obtainable by well-knownprocedures) and the bisamidine is built from this. In preparingbisamidines of Structure 3 where Z is methylene, the combination unit 12(obtainable by well-known procedures) is employed, and the sequence ofprocess steps used is otherwise analogous to that used for biasamidineswhere Z is sulphur.

Care should be taken to use a sequence where one unit reagent orcombination is not incompatible with another because of side-reactionswith the group X¹ and X² present in another reagent. Thus a unit reagentor combination containing the reactive group --SMe is liable to reactwith the group X¹ or X² in a unit reagent or combination where this is afree imino group NH, and this is avoided by using a reagent with aprotective imino group, such as benzoylimino NCOPh. Other reactivegroups present, for instance an amino substituent of the heterocycle canbe temporarily protected.

Where the groups X¹ and/or X² in the bisamidine are NY, where Y ishydroxy or lower alkyl, these are formed from the correspondingcompounds where X¹ and/or X² are sulphur (neither X¹ nor X² being NH) byalkylation to the intermediate alkylthio compounds, for instance withmethanolic hydrogen chloride or methyl iodide, and hydrolysis orreaction with hydroxylamine or the appropriate primary alkylamine. Wherein the bisamidines X¹ and X² are NCONH₂, these are obtained by partialhydrolysis of the corresponding compounds where X¹ and X² are NCN.Bisamidines where X¹ and/or X² are NH can also be obtained by thehydrolysis of compounds where X¹ and/or X² are NCN or NCOPh.

In accordance with the above, the invention provides a process forpreparing bisamidines of Structure 3, in which a compound of structureHet-(CH₂)_(m) E, where E is chlorine, Z(CH₂)_(n) NH₂, Z(CH₂)_(n) NHCX¹SA, Z(CH₂)_(n) NHCX¹ NH(CH_(2;l) )_(q) NH₂, or Z(CH₂)_(n) NHCX¹NH(CH₂)_(q) NHCX² SA is reacted with the complementary compound ofstructure GNHR, where G is HS(CH₂)_(n) NHCX¹ NH(CH₂)_(q) NHCX² --, ASCX¹NH(CH₂)_(q) NHCX² --, NH₂ (CH₂)_(q) NHCX² --, ASCX² -- or hydrogen,where A is lower alkyl and each of X¹ and X² is S, CHNO₂, NH (includingprotected NH) or NCN, provided that where E is chlorine, Z is sulphur;and if required, wherein the reaction product X¹ and/or X² are (a) S,these are converted by alkylation and reaction either with hydroxylamineto form a compound where X¹ and/or X² are NOH or with a primary loweralkylamine to form a compound where X¹ and/or X² are NY where Y is loweralkyl; (b) NCN, these are hydrolysed to form a compound where X¹ and/orX² are carbamoyl or NH; and (c) protected NH, these are subjected to adeprotection step to form a compound where X¹ and/or X² are free NH.

The complementary pairs of reagents are thus

Het-(CH₂)_(m) Cl and HS(CH₂)_(n) NHCX¹ NH(CH₂)_(q) NHCX² NHR

Het-(CH₂)_(m) Z(CH₂)_(n) NH₂ and ASCX¹ NH(CH₂)_(q) NHCX² NHR

Het-(CH₂)_(m) Z(CH₂)_(n) NHCX¹ SA and NH₂ (CH₂)_(q) NHCX² NHR

Het-(CH₂)_(m) Z(CH₂)_(n) NHCX¹ NH(CH₂)_(q) NH₂ and ASCX² NHR

Het-(CH₂)_(m) Z(CH₂)_(n) NHCX¹ NH(CH₂)_(q) NHCX² SA and NH₂ R

The steps in the above process with the pairs of reagents correspond toend-steps in the sequence of structure building described earlier as thecombination of structural units 1 with 23456 12 with 3456, 123 with 456,1234 with 56, and 12345 with 6.

In each instance the reaction involved is formation of a bond betweencarbon and a hetero atom by elimination of the groups at the site ofjunction: with the first pair the reaction eliminates HCl (in practiceas NaCl) to effect formation of a C-S bond, and with the others thereaction eliminates the compound ASH to effect formation of a C-N bond.

The use of obvious chemical equivalents of the chlorine (such as bromineand arylsulphonyloxy) and the group SA (such as arylthio, aralkylthio,lower alkoxy, aryloxy and alkylsulphinyl) in the above process is to beconsidered as within the scope of the claims of the present invention.

Preferably A is a methyl group.

Compounds of Structure 3 where X¹ and/or X² are NCN can also be preparedfrom the corresponding compounds where X¹ and/or X² are sulphur,(neither X¹ nor X² being NH), by alkylation and subsequent reaction ofthe alkylthio compound obtained with cyanamide and a strong base such assodium methoxide or potassium t-butoxide; or by reaction with a salt ofcyanamide with a heavy metal such as lead, cadmium or mercury in asolvent such as acetonitrile or dimethylformamide.

In converting a compound of Structure 3 where X¹ and/or X² are NCN to acorresponding compound where they are NCONH₂ and NH respectively, acidhydrolysis can be used under mild conditions to effect partialhydrolysis or more severe ones to effect full hydrolysis.

In converting a compound of Structure 3 where X¹ and/or X² are protectedNH groups to a corresponding compound where they are free imino groups,conditions suitable for removing the protecting group are employed; forinstance acid hydrolysis can be used to remove a benzoyl group.

The compounds of Structure 3 that are pharmacologically active are thoseother than the compounds in which X¹ and X² are protected imino groups:these latter are useful as intermediates for conversion to the activecompounds. The active compounds block histamine H₂ -receptors; that is,they inhibit the biological actions of histamine which are not inhibitedby "antihistamines" such as mepyramine but are inhibited by burimamide.For example, they inhibit histamine-stimulated secretion of gastric acidfrom the lumen-perfused stomachs of rats anaesthetised with urethane, atdoses of from 0.5 to 256 micromoles per kilogram intravenously. Theiractivity as histamine H₂ -antagonists is also demonstrated by theirability to inhibit other actions of histamine which are not mediated byhistamine H₁ -receptors. For example, they inhibit the actions ofhistamine on the isolated guinea pig atrium and isolated rat uterus.They inhibit the basal secretion of gastric acid and also thatstimulated by pentagastrin or by food. In a conventional test such asthe measurement of blood pressure in the anaesthetised cat, at doses offrom 0.5 to 256 micromoles per kilogram intravenously, they inhibit thevasodilator action of histamine. The potency of the compounds isillustrated by an effective dose producing 50% inhibition of gastricacid secretion in the anaesthetised rat and 50% inhibition ofhistamine-induced tachycardia in the isolated guinea pig atrium (lessthan 10⁻⁴ Molar).

For therapeutic use, the pharmacologically active compounds willnormally be administered as a pharmaceutical composition comprising atleast one such compound in the basic form or in the form of its additionsalt with a pharmaceutically acceptable acid and in association with apharmaceutical diluent or carrier. Such addition salts include thosewith hydrochloric, hydrobromic, hydriodic, sulphuric and maleic acidsand may conveniently be formed from the corresponding bases by standardprocedures, for example by treating the base with an acid in a loweralkanol or by the use of ion exchange resins to form the required salteither directly from the base or from a different addition salt.

Pharmaceutical compositions comprising a pharmaceutical carrier and apharmacologically-active compound of the invention of Structure 3 in thebasic form or in the form of its pharmaceutically-acceptable acidaddition salts are also objects of this invention. The pharmaceuticalcarrier employed can be a solid or liquid. Examples of solid carriersare lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia,magnesium stearate and stearic acid. Examples of liquid carriers aresyrup, peanut oil, olive oil and water.

If a solid carrier is used, the composition can be prepared in the formof a tablet, capsule, troche or lozenge. The amount of solid carrier ina unit dosage form is generally from about 25 mg to about 300 mg. If aliquid carrier is used, the composition can be in the form of a syrup,emulsion, soft gelatin capsule, a sterile injectable liquid containedfor example in an ampoule, or an aqueous or non-aqueous liquidsuspension. The pharmaceutical compositions are prepared by conventionaltechniques involving procedures such as mixing, granulating andcompressing or dissolving the ingredients as appropriate to the desiredpreparation.

The active ingredient is present in the composition in an effectiveamount to block histamine H₂ -receptors. Preferably, each dosage unitcontains the active ingredient in an amount of from about 50 mg to about250 mg.

Methods of blocking histamine H₂ -receptors which comprise administeringto an animal a pharmacologically active compound of the invention ofStructure 3 in the basic form or in the form of itspharmaceutically-acceptable acid addition salts, including thepharmaceutical compositions containing them, are also objects of theinvention.

The active ingredient is preferably administered from one to six timesper day. The daily dosage regimen will generally be from about 150 mg toabout 1500 mg.

The route of administration may be oral or parenteral.

The intention is illustrated but not limited by the following Examplesin which temperatures are in °C.

EXAMPLE 1

N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-S-methylisothioureahydriodide (3.72 g) and N-(2-aminoethyl)-N'-cyano-N"-methylguanidine(1.41 g) were dissolved in isopropyl alcohol (25 ml) and the mixture washeated under reflux for 6 hours. The solution was allowed to cool andthe solid which crystallised not was filtered off and recrystallisedfrom ethanol/isopropyl alcohol to give1-[N'-(2-(5-methyl-4-imidazolyl)methylthio)ethyl)guanidino]-2-[N'-cyano-N"-methylguanidino]ethaneas the hydriodide (1.8 g), m.p. 164°-165°: Found: C, 33.85; H, 5.3; N,26.8: S, 6.8: I, 27.15. C₁₃ H₂₃ N₉ S.HI requires: C, 33.55; H, 5.2: N,27.1: S, 6.9: I, 27.3%.

EXAMPLE 2

(a) Reaction ofN-cyano-N'-[2-((5-methyl-4-imidazolyl)-methylthio)ethyl]-S-methylisothioureawith excess 1,2-diaminoethane at room temperature gaveN-cyano-N'-(2-aminoethyl)-N"-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]guanidine,m.p. 164°-167°.

(b) The product of (a) (8.4 g) and N-cyanodimethyldithioimidocarbonate(5.8 g) were dissolv;ed in isopropyl alcohol (50 ml) and the mixture washeated under reflux for 1 hour, and allowed to cool. Solid was filteredoff, washed with ether and recrystallised from methanol to giveN-cyano-N'-[2-(N-cyano-S-methylisothioureido)ethyl]-N"-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]guanidine(8.1 g), m.p. 115°-116°. This latter compound (4.05 g) was dissolved in50 ml of a 33% solution of methylamine in ethanol and the mixture washeated under reflux for 3 hours, and evaporated to an oil.Crystallisation from aqueous isopropyl alcohol and recrystallisationfrom water gave1-[N'-cyano-N"-(2-(5-methyl-4-imidazolyl)methylthio)ethyl)guanidino]-2-[N'-cyano-N"-methylguanidino]ethane(1.0 g) m.p. 120°-124°: Found: C, 46.35; H, 6.1: N, 38.7: S, 8.8. C₁₄H₂₂ N₁₀ S requires: C, 46.4; H, 6.1; N, 38.7; S, 8.9%.

EXAMPLES 3 to 13

A process is carried out as in Example 1, but using correspondingamounts of each of the following compounds instead ofN-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-S-methylisothiourea:

N-[2-((4-imidazolyl)methylthio)ethyl]-S-methylisothiourea,

N-[2-((5-bromo-4-imidazolyl)methylthio)ethyl]-S-methylisothiourea,

N-[2-((3-chloro-2-pyridyl)methylthio)ethyl]-S-methylisothiourea,

N-[2-((3-methoxy-2-pyridyl)methylthio)ethyl]-S-methylisothiourea,

N-[2-((2-thiazolyl)methylthio)ethyl]-S-methylisothiourea,

N-[2-((3-isothiazolyl)methylthio)ethyl]-S-methylisothiourea,

N-[2-((2-oxazolyl)methylthio)ethyl]-S-methylisothiourea,

N-[2-((3-isoxazolyl)methylthio)ethyl]-S-methylisothiourea,

N-[2-((2-(1,3,4)-thiadiazolyl)methylthiolethyl]-S-methylisothiourea,

N-[2-((3-(1,2,4)-triazolyl)methylthio)ethyl]-S-methylisothiourea and

N-[4-(4-imidazolyl)butyl]-S-methylisothiourea.

The products obtained are respectively:

    ______________________________________                                        Ex-                                                                           am-                                                                           ple                                                                           No.                                                                           ______________________________________                                        3.   1-[N'--(2-((4-imidazolyl)methylthio)ethyl)guanidino]-2-                       [N'--cyano-N"--methylguanidino]ethane                                    4.   1-[N'--(2-((5-bromo-4-imidazolyl)methylthio)ethyl)guani-                      dino]-2-[N'--cyano-N"--methylguanidino]ethane                            5.   1-[N'--(2-((3-chloro-2-pyridyl)methylthio)ethyl)guanidino]-                   2-[N'--cyano-N"--methylguanidino]ethane                                  6.   1-[N'--(2-((3-methoxy-2-pyridyl)methylthio)ethyl)guani-                       dino]-2-[N'--cyano-N"--methylguanidino]ethane                            7.   1-[N'--(2-((2-thiazolyl)methylthio)ethyl)guanidino]-2-N'--                    cyano-N"--methylguanidino]ethane                                         8.   1-[N'--(2-((3-isothiazolyl)methylthio)ethyl)guanidino]-2-                     [N'--cyano-N"--methylguanidino]ethane                                    9.   1-[N'--(2-((2-oxazolyl)methylthio)ethyl)guanidino]-2-                         [N'--cyano-N"--methylguanidino]ethane                                    10.  1-[N'--(2-((3-isoxazolyl)methylthio)ethyl)guanidino]-2-                       [N'--cyano-N"--methylguanidino]ethane                                    11.  1-[N'--(2-((2-(1,3,4)-thiadiazolyl)methylthio)ethyl)-                         guanidino]-2-[N'--cyano-N"--methylguanidino]ethane                       12.  1-[N'--(2-((3-(1,2,4)-thiazolyl)methylthio)ethyl)guanidino]-                  2-[N'--cyano-N"--methylguanidino]ethane                                  13.  1-[N'--(4-(4-imidazolyl)butyl)guanidino]-2-[N'--                              cyano-N"--methylguandino]ethane                                          ______________________________________                                    

EXAMPLES 14 to 19

Use ofN-cyano-N'-[2-((5-methyl-4-imidazolyl)methylthio)-ethyl]-S-methylisothioureain the process of Example 2(a) with each of 1,3-diaminopropane,1,4-diaminobutane, 1,7-diaminoheptane, 1,8-diaminooctane,1,10-diaminodecane and 1,12-diaminododecane, yields respectively thefollowing compounds:

N-cyano-N'-(3-aminopropyl)-N"-[2-((5-methyl-4-imidazolyl)-methylthio)ethyl]guanidine

N-cyano-N'-(4-aminobutyl)-N"-[2-((5-methyl-4-imidazolyl)-methylthio)ethyl]guanidine,m.p. 109°-111°

N-cyano-N'-(7-aminoheptyl)-N"-[2-((5-methyl-4-imidazolyl)-methylthio)ethyl]guanidine,m.p. 84°-87°

N-cyano-N'-(8-aminooctyl)-N"-[2-((5-methyl-4-imidazolyl)-methylthio)ethyl]guanidine,m.p. 122°-124°

N-cyano-N'-(10-aminodecyl)-N"-[2-((5-methyl-4-imidazolyl)-methylthio)ethyl]guanidine

N-cyano-N'-(12-aminododecyl)-N"-[2-((5-methyl-4-imidazolyl)-methylthio)ethyl]guanidine.

On reaction of these products first withN-cyanodimethyldithioimidocarbonate and then with methylamine accordingto the procedure of Example 2(b) the following products are obtained:

    ______________________________________                                        Ex-                                                                           am-                                                                           ple                                                                           No.                                                                           ______________________________________                                        14.  1-[N'--cyano-N"--(2-((5-methyl-4-imidazolyl)methylthio)-                      ethyl)guanidino]-3-[N'--cyano-N"--methyl-                                     guanidino]propane                                                        15.  1-[N'--cyano-N"--(2-((5-methyl-4-imidazolyl)methylthio)-                      ethyl)guanidino]-4-[N'--cyano-N"--methylguanidino]butane                 16.  1-[N'--cyano-N"--(2-((5-methyl-4-imidazolyl)methylthio)-                      ethyl)guanidino]-7-[N'--cyano-N"--methylguanidino]                            heptane                                                                  17.  1-[N'--cyano-N"--(2-((5-methyl-4-imidazolyl)methylthio)-                      ethyl)guanidino]-8-[N'--cyano-N"--methylguanidino]                            octane, m.p. 79-81°                                               18.  1-[N'--cyano-N"--(2-((5-methyl-4-imidazolyl)methylthio)-                      ethyl)guanidino]-10-[N'--cyano-N"--methylguanidino]                           decane                                                                   19.  1-[N'--cyano-N"--(2-((5-methyl-4-imidazolyl)methylthio)-                      ethyl)guanidino]-12-[N'--cyano-N"--methylguanidino]dodecane              ______________________________________                                    

EXAMPLE 20

(a) A mixture of 1,8-diaminooctane (14.1 g) withN-cyano-N'-methyl-S-methyl isothiourea (5.2 g) was maintained at 60° for5 hours to give a solid product which was washed with ether andrecrystallised from acetonitrile/ether to giveN-cyano-N'-methyl-N"-(8-aminooctyl)guanidine (5.3 g) m.p. 81°-83°.

(b) The product of (a) (2.22 g) andN-cyano-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-S-methylisothiourea(2.4 g) were heated in pyridine (25 ml) under reflux for 12 hours.Evaporation of the reaction mixture yielded an oily residue which waschromatographed on a silica gel column with a 1:4 mixture of isopropylalcohol and ethyl acetate. Evaporation of the eluent gave1-[N'-cyano-N"-(2-((5-methyl-4-imidazolyl)-methylthio)ethyl)guanidino]-8-[N'-cyano-N"-methylguanidino]octane(0.7 g) as a glass. This compound was shown to be identical with thatprepared in Example 17.

EXAMPLE 21

The product of Example 1 was heated under reflux with an excess of 12 Nhydrochloric acid for 6 hours and the mixture then evaporated todryness. The residue was recrystallised from isopropyl alcohol to give1-[N'-(2-((5-methyl-4-imidazolyl)-methylthio)ethyl)guanidino]-2-[N'-methylguanidino]ethanetrihydrochloride, m.p. 194°-200°.

EXAMPLE 22

The product of Example 20 was heated under reflux with an excess of 12 Nhydrochloric acid for 10 hours and evaporated to low volume. Thissolution was basified by the addition of a basic polyamine polystyreneion-exchange resin cross-linked with 2% divinylbenzene (OH⁻ form) andthe solution was evaporated to dryness to give1-[N'-(2-((5-methyl-4-imidazolyl)methylthio)ethyl)guanidino]-8-[N'-methylguanidino]octane.To this product was added an excess of hydrochloric acid and thesolution evaporated to dryness to give the trihydrochloride which was aglass: nmr: (100 MHz. D₂ O)1.4(m,(CH₂)₆), 2.32(s,CH₃), 2.76(m, (CH₂ S)),2.84(s, (NHCH₃), 3.19(m(2xNCH₂)), 3.42(m,NCH₂), 3.89(s,CH₂ S),8.59(s,Imid2-H).

EXAMPLE 23

A solution ofS-methyl-N-[2-((5-methyl-4-imidazolyl)-methylthio)ethyl]dithiocarbamate(5 g) in ethanol (60 ml) is added to a solution of sodium (0.3 g) inethanol (100 ml) and after filtration a solution of excess1,8-diaminooctane (1.4 g) is ethanol (30 ml) is added and the mixtureheated under reflux for 24 hours. Concentration of this reaction mixtureyieldsN-(8-aminooctyl)-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-thiourea,which when reacted first with N-cyanodimethyldithioimidocarbonate andthen with methylamine according to the procedure of Example 2(b), yields1-[N'-((2-(5-methyl-4-imidazolyl)methylthio)ethyl)thioureido]-8-[N'-cyano-N"-methylguanidino]octane.

EXAMPLE 24

Use in the process of Example 2(b) of 1,1-dimethylthio-2-nitroethyleneinstead of N-cyanodimethyldithioimidocarbonate gives1-[2-(N'-cyano-N"-(2-((5-methyl-4-imidazolyl)methylthio)-ethyl)guanidino]ethylamino]-1-methylamino-2-nitroethylene.

EXAMPLE 25

Reaction ofN-(8-aminooctyl)-N'-[2-((5-methyl-4-imidazolyl)-methylthio)ethyl]thiourea(see Example 22) with N,S-dimethyldithiocarbamate yields1-[N'-(2-((5-methyl-4-imidazolyl)methylthio)ethyl)thioureido]-8-[N'-methylthioureido]octane.

EXAMPLE 26

Dry hydrogen chloride is bubbled through a solution of the product ofExample 25 in methanol at 80° and the solvent removed, to give1-[N'-(2-((5-methyl-4-imidazolyl)methylthio)-ethyl)-S-methylisothioureido]-8-[N',S-dimethylisothioureido]-octane.Reaction of this with at least two equivalents of hydroxylaminehydrochloride yields1-[N'-hydroxy-N"-(2-((5-methyl-4-imidazolyl)methylthio)ethyl)guanidino]-2-[N'-hydroxy-N"-methylguanidino]ethane.

EXAMPLE 27

Reaction of the bis-S-methyl intermediate of Example 26 with methylamineaccording to the procedure of Example 2(b) yields1-[N'-methyl-N"-(2-((5-methyl-4-imidazolyl)methylthio)-ethyl)guanidino]-8-[N',N"-dimethylguanidino]octane.

EXAMPLE 28

Hydrolysis of the product of Example 2 with dilute hydrochloric acid at40° yields1-[N'-carbamoyl-N"-(2-((5-methyl-4-imidazolyl)methylthio)ethyl)guanidino]-2-[N'-carbamoyl-N"-methylguanidino)ethane.

EXAMPLE 29 and 30

Use in the process of Example 2 of ammonia and ethylamine instead ofmethylamine gives respectively:1-[N'-cyano-N"-(2-((5-methyl-4-imidazolyl)methylthio)ethyl)-guanidino]-2-[N'-cyanoguanidino]ethane(Example 29)1-[N'-cyano-N"-(2-((5-methyl-4-imidazolyl)methylthio)ethyl)-guanidino]-2-[N'-cyano-N"-ethylguanidino]ethane(Example 30).

EXAMPLE 31

(a) N-Cyano-N'-methyl-N"-(8-aminooctyl)guanidine (see Example 20) isheated under reflux with an equivalent amount ofN-cyanodimethyldithioimidocarbonate in isopropyl alcohol for 1 hour togiveN-cyano-N'-[8-(N-cyano-S-methylisothioureido)-octyl]-N"-methylguanidine.

(b) The latter product is mixed with excess4-(2-aminoethylthiomethyl)5-methylimidazole and heated to 130° for 6hours to give the product of Example 20, which is isolated as theredescribed.

EXAMPLE 32

(a) To the isolated intermediate of Example 31(a) suspended in ethanolis added an equivalent amount of cysteamine hydrochloride is water: anequivalent amount of aqueous sodium hydroxide is added to liberate thecysteamine and the mixture heated under reflux for 1 hour. Ethanol isremoved by evaporation and water added to precipitate1-N'-cyano-N"-(2-mercaptoethyl)guanidino]-8-[N'-cyano-N"-methylguanidino]octane.

(b) A solution of the dried product of (a) (1 mol) in dry ethanol isadded to sodium ethoxide (2 mols) in ethanol under nitrogen withstirring, and stirring continued for 1 hour at ambient temperature.Powdered 5-methyl-4-chloromethylimidazole hydrochloride (1 mol) wasadded gradually to the solution which was stirred at ambient temperaturefor 1 hour and then heated at reflux temperature for 30 minutes, cooled,filtered and the product of Example 20 isolated as there described.

EXAMPLE 33

(a) 1,8-Diaminooctane (14.1 g) and N-cyanodimethyldithiomidocarbonate(29.2 g) is isopropyl alcohol (100 ml) were heated under reflux for 2hours: the reaction mixture was cooled and the product crystallised fromsolution, and recrystallised from dimethylformamide/ether to givebis-1,8-(N-cyano-S-methylisothioureido)octane (25 g), m.p. 195°-197°.

(b) The product of (a) (17 g) and4-(2-aminoethylthiomethyl)-5-methylimidazole (6.8 g) were dissolved in amixture of pyridine (75 ml) and isopropyl alcohol (20 ml), and themixture heated under reflux for 16 hours. The product,1-[N'-cyano-N"-(2-(5-methyl-4-imidazolyl)methylthio)ethyl)-guanidino]-8-[N'-cyano-S-methylthioureido]octane(2.2 g) m.p. 92°-100° crystallised out on cooling.

(c) The product of (b) in ethanol is heated under reflux withmethylamine for 2 hours, and then evaporated to dryness to give1-[N'-cyano-N"-(2-(5-methyl-4-imidazolyl)methylthio)-ethylguanidino]-8-[N'-cyano-N"-methylguanidino]octane.

EXAMPLE 34

(a) A mixture of N-benzoyl-N'-methyl-S-methylisothiourea and an excessof 1,8-diaminooctane is maintained at 60° for 5 hours to give a solidproduct which is washed with ether to leaveN-benzoyl-N'-methyl-N"-(8-aminooctyl)guanidine.

(b) This benzoylguanidine is used instead of theN-(2-aminoethyl)-N'-cyano-N"-methylguanidine in the process of Example1, employing an equivalent amount, and there is obtained1-[N-(2-((5-methyl-4-imidazolyl)methylthio)ethyl)-guanidino]-8-[N'-benzoyl-N"-methylguanidino]octane.

EXAMPLE 35

The product of Example 24 is heated in ION hydrochloric acid at 100° for6 hours, cooled, filtered to remove benzoic acid: the solution isevaporated to dryness to give1-[N'-(2-((5-methyl-4-imidazolyl)methylthio)ethyl)guanidino]-8-[N'-methylguanidino]octanetrihydrochloride.

EXAMPLE 36

The process of Example 33(a) is carried out using the equivalent amountof N-benzoyl-dimethyldithioimidocarbonate instead ofN-cyanodimethyldithioimidocarbonate, to givebis-1,8-(N-benzoyl-S-methylisothioureido)octane: this is used in theprocess of Example 23(b) to give1-[N'-benzoyl-N"-(2-(5-methyl-4-imidazolyl)methylthio)ethyl)guanidino]-8-[N'-benzoyl-S-methylthhiouredio]octane,which is reacted with methylamine to give1-[N'-benzoyl-N"-(2-(5-methyl-4-imidazolyl)-methylthio)ethylguanidino]-8-[N'-benzoyl-N"-methylguanidino]-octane.

EXAMPLE 37

Hydrolysis or the product of Example 36 with hydrochloric acid using theprocedure of Example 22 gives the product of Example 22.

EXAMPLE 38

A pharmaceutical composition is prepared from the following ingredients:

    ______________________________________                                        1-[N'--cyano-N"--(2-((5-methyl-4-imidazolyl)-                                 methylthio)ethyl)guanidino]-2-[N'--cyano-N"--                                 methylguanidino]ethane      150 mg                                            Sucrose                     75 mg                                             Starch                      25 mg                                             Talc                        5 mg                                              Stearic acid                2 mg                                              ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

EXAMPLE 39

An injectable pharmaceutical composition is prepared by dissolving1-[N'-(2-(5-methyl-4-imidazolyl)methylthio)-ethylguanidino]-8-[N'-methylguanidino]octanetrihydrochloride (100 g) in sterile water (2 liters). From it areprepared ampoules containing 100 mg of active ingredients.

Similarly, other compounds of Structure 3 can be formulated aspharmaceutical compositions by the procedures of Examples 38 and 39.

The pharmaceutical compositions prepared in the foregoing Examples areadministered to a subject within the dose range given above to blockhistamine H₂ -receptors.

What is claimed is:
 1. A compound of the structure ##STR5## in which Hetis a 5-membered fully unsaturated heterocycle containing at least onenitrogen atom, said heterocycle being oxazole, isoxazole, 1,2,4-triazoleor 1,2,5-thiadiazole, and optionally substituted by lower alkyl,trifluoromethyl, hydroxymethyl, halogen or lower alkoxy, or1,3,4-thiadiazole optionally substituted by lower alkyl,trifluoromethyl, hydroxymethyl, halogen, lower alkoxy or amino, saidheterocycle being attached at a ring carbon;Z is sulphur or methylene; mis 0, 1 or 2, n is 2 or 3, and m+n is 3 or 4; R is hydrogen or loweralkyl; each of X¹ and X² is sulphur, a nitromethylene group CHNO₂, or animino group NY, where Y is hydrogen, hydroxy, lower alkyl, cyano orcarbamoyl CONH₂ ; and q is from 2 to 12; in the form of the free base orits pharmaceutically-acceptable acid addition salts.
 2. A compoundaccording to claim 1, in which the group (CH₂)_(m) is linked to a carbonatom of the heterocycle adjacent to a nitrogen atom.
 3. A compoundaccording to claim 1, in which Z is sulphur, m is 1 and n is
 2. 4. Acompound according to claim 1, in which q is
 2. 5. A compound accordingto claim 1, in which q is
 8. 6. A compound according to claim 1, inwhich R is methyl.
 7. A compound according to claim 1, in which both X¹and X² are NY.
 8. A compound according to claim 1, in which both X¹ andX² are NH.
 9. A compound according to claim 7, in which both X¹ and X²are NCN.
 10. A pharmaceutical composition to block histamine H₂-receptors comprising in an effective ammount to block said receptors acompound of claim 1 in combination with a pharmaceutically-acceptablediluent or carrier.
 11. A method of blocking histamine H₂ -receptorswhich comprises administering to an animal in need thereof in aneffective amount to block said receptors a compound of claim 1.